Dipeptidyl peptidase IV (DPP-IV) is a multifunctional type II transmembrane glycosylated protein that is widely expressed in the tissues of various mammals, which is a type of T cell activation antigen CD26 and is also a type of adenosine deaminase (ADA) binding protein. The single chain of the human DPP-IV (hDPP-IV) consists of 766 amino acids, which are divided into 5 structural domains: cytomere domain (1-6), transmembrane domain (7-28), highly glycosylated domain (29-323), cysteine-rich domain (324-551) and catalytic domain (552-766), and different species slightly differ from each other in terms of the lengths of these domains. Soluble DPP-IV is a homodimer of about 210-290 kDa and can also polymerize to form a complex of up to 900 kDa. DPP-IV binds with membrane via a hydrophobic helix formed by highly glycosylated domain and cysteine-rich domain at amino-terminal, and its serine protease domain at carboxyl-terminal is homologous to α/δhydrolase. The dimer form of DPP-IV is a precondition that it takes effect (heterodimer is a type of fibroblast activated protein FAPα).
It is generally agreed that DPP-IV plays an important role in neuropeptide metabolism, T cell activation, cancer cell and endothelial attachment and entry of HIV into lymphocyte. DPP-IV can specifically cleave a dipeptide from N-terminal of a peptide in which the amino acid next to the last is mainly proline, alanine or hydroxyproline. The substrate by which DPP-IV takes effect includes two types of incretins that play an important role in the course of T2DM immune response signal transduction: segment of glucagon-like peptide 1 (GLP-17-36) and gastric inhibitory peptide (GIP1-42). GLP-1 and GIP are incretins that are respectively secreted by gastric mucosa L cells and K cells in response to carbohydrates and fats taken in, and play an important role in stabilizing postprandial blood sugar concentration. After dining, gastric mucosa stress-secretes GLP-1 and GIP, both of which act on pancreas to strengthen glucose-induced insulin secretion, and modulate blood sugar concentration. Whereas, DPP-IV in vivo may hydrolyze them to generate the corresponding amino-terminal amputated GIP3-42 and GLP-19-36, so that they will lose their insulin-inducing activity. Thus it can be seen, an inhibitor of DPP-IV is capable of strengthening the activity of GIP and GLP-1, and correspondingly improving the sugar tolerance level.
The DPP-IV deficient mouse experimental results obtained by Marguet et al and Conarello et al demonstrated that DPP-IV deficient mouse could completely survive and possessed normal phenotype; meanwhile, as compared with wild-type mouse, DPP-IV deficient mouse also exhibited a higher sugar tolerance and a higher blood insulin, GLP-1 concentration.
To sum up, inhibiting plasma DPP-IV activity is effective for reducing blood sugar concentration, which acts in at least three mechanisms listed below: firstly, to protect the activity of insulin: under physiological condition, the half life of intact GLP-1 in circulating blood is less than 1 min, and inactive metabolite of GLP-1 after degradation with DPP-IV can bind with GLP-1 receptor to antagonize active GLP-1, to thereby shorten the actuation duration of GLP-1 that is injected alone, while an inhibitor of DPP-IV can completely protect endogenous and even exogenous GLP-1 from deactivation by DPP-IV. It is known that GLP-1 has various physiological activities, including promoting expression of insulin gene, promoting growth of β cells, inhibiting secretion of glucagons, gaining a full abdomen feeling, reducing ingestion, and inhibiting gastric emptying, to thereby normalize the blood sugar level; and an inhibitor of DPP-IV can reduce the antagonistic action of GLP-1 metabolite in addition to increasing the level of GLP-1. Besides, GIP secreted by k cells at upper part of small intestine, by acting on G protein-coupled receptor, increase the activity of adenyl cyclase, activate enzyme A2. to increase calcium ion level in cells, and promote release of insulin. GIP can also promote transcription and translation of proinsulin gene, up-regulate glucose transfer of plasma membrane and increase activity of β cell hexokinase, thus GIP is effective for treating type II diabetes (T2DM). However, being similar to GLP-1, endogenous GIP is also rapidly deactivated by DPP-IV. Deacon et al revealed that, after intravenous injection of GIP to a pig, the immunocompetence of intact GIP shown by radioimmunoassay was only 14.5%. When an inhibitor of DPP-IV was used, the immunocompetence of GIP was increased to 49%. This demonstrated that although DPP-IV is not the unique enzyme that degrades GIP in vivo, it plays an important role in the deactivation of GIP. Clearly, an inhibitor of DPP-IV can protect active incretin so that the later can take its effect.
Secondly, to stimulate the regeneration of islet β cells: Pospisilik et al administered P32/98 (an inhibitor of DPP-IV) to a streptozotocin-induced DM male mouse, 2 times/d; after 7 weeks, it was observed by immunohistochemical analysis that, as compared with the control group, the number of islets was increased by 35%, the number of overall β cells was increased by 120%, the fraction of islet β cells was increased by 12%, and the plasma insulin level was approaching to normal. The effect of an inhibitor of DPP-IV for stimulating the regeneration of insulin and increasing the survival of β cells may be due to that it improves the binding between GLP-1 and GLP-1 receptor on the surface of nestin-positive islet-derived progenitor (NIP) cells in islets, which thereby promotes the NIP cells to differentiate into islet cells.
Thirdly, to improve sugar tolerance and insulin sensitivity: it was shown by study that an inhibitor of DPP-IV was not only effective for treating DM, but also could take a preventive effect in terms of postponing the occurrence and development of DM. Sudre et al studied the treatment of obese mouse by using FE 999011 (a long-acting inhibitor of DPP-IV), and proved that FE 999011 slowed down the release of glucose in a dose-dependent manner, and the application of FE 999011, 10 mg/kg, 2 times/d, could increase the sugar tolerance. A long-term treatment by using the same dose as above-mentioned could postpone the occurrence of hyperglycemia in obese mouse by 21 d, and meanwhile could enhance the symptoms such as polydipsia and polyphagia, reduce the occurrence of hypertriglyceridemia, and prevent increasing of free fatty acids in blood; moreover, after the treatment, the basic plasma GLP-1 level was increased, and the pancreatic GLP-1 receptor gene expression was obviously up-regulated. Thus, the researchers considered that an inhibitor of DPP-IV could postpone the development of impaired glucose tolerance into type II diabetes. It was also suggested in other studies that the application of an inhibitor of DPP-IV could improve impaired glucose tolerance, increase insulin sensitivity, and improve the response of β cells to glucose.
Thus, an inhibitor of DPP-IV is capable of treating type II diabetes and other diseases modulated by DPP-IV.